ABSTRACT Chronic pain afflicts >10% of US adults, with women being disproportionately affected, and constitutes a serious public health threat associated with overuse/misuse of opioid pain medications. Thus, new pain therapies based on detailed understanding of chronic pain mechanisms are needed as alternatives to opioid analgesics. Central sensitization is an important underlying contributor to chronic pain states, but it remains poorly understood how central sensitization persists when the inciting injury has apparently resolved. This proposal addresses female- specific mechanisms that maintain persistent central sensitization using a novel animal model that transitions from acute to chronic pain. This new model is based on the widely-used intradermal capsaicin injection model that normally develops short-lasting (1-3 days) central sensitization, resulting in mechanical hypersensitivity in areas outside the capsaicin injection site. We found that subsequent innocuous stimulation (e.g., warmth) of the capsaicin-injected hindpaw extended the central sensitization to more than two weeks, thus modeling pathological pain states where acute injury-induced temporary pain transitions to chronic pain despite resolution of the original injury. Both male and female mice develop persistent central sensitization, but the underlying mechanism(s) is sexually dimorphic in that a local anesthesia of the original injury site inhibits the persistent central sensitization only in females. This finding is reminiscent of clinical reports on 5 cases (4 women, 1 man) of complex regional pain syndrome in which local anesthesia of previous injury sites abolished mechanical hypersensitivity remote from the sites. Based on this observation and the literature, we hypothesize that the maintenance of central sensitization in females depends on persistent, ongoing peripheral nerve activity at the original injury site. We will test this hypothesis using the new female chronic pain model with behavioral, immunohistochemical, and electrophysiological approaches and determine the peripheral afferent types persistently active at the original injury site (Aim 1); the underlying molecular mechanism(s) of this persistent afferent activity (Aim 2); and central components contributing to the central sensitization maintained by persistent, ongoing afferent nerve activity (Aim 3). The results of this project will provide new knowledge of previously unrecognized female-specific chronic pain mechanisms and reveal peripheral and central targets for potential non-opioid chronic pain therapies in women, contributing to development of strategies to combat the ?opioid epidemic? caused by overuse/misuse of opioid analgesics.